tbuckley/cabot-search huggingface dataset:
FPR2 Shapes an Immune-Excluded Pancreatic Tumor Microenvironment and Drives T-cell Exhaustion in a Sex-Dependent Manner
Authors: Fei He, Apple H.M. Tay, Ahmed Calandigary, Enana Malki, Sayaka Suzuki, Tianjie Liu, Qi Wang, Carlos Fernández-Moro, Marina Kaisso, Peter Olofsson-Sahl, Marit Melssen, Siu Kwan Sze, Mikael Björnstedt, Matthias J. Löhr, Mikael C.I. Karlsson, Rainer Heuchel, Dhifaf Sarhan
Journal: Cancer Research (2023)

Sex-driven immune differences can affect tumor progression and the landscape of the tumor microenvironment. Deeper understanding of these differences in males and females can inform patient selection to improve sex-optimized immunotherapy treatments. In this study, single-cell RNA sequencing and protein analyses uncovered a subpopulation of myeloid cells in pancreatic lesions associated with an immune-excluded tumor phenotype and effector T-cell exhaustion exclusively in females. This myeloid subpopulation was positively correlated with poor survival and genetic signatures of M2-like macrophages and T-cell exhaustion in females. The G-protein coupled receptor formyl peptide receptor 2 (FPR2) mediated these immunosuppressive effects. In vitro, treatment of myeloid cells with a specific FPR2 antagonist prevented exhaustion and enhanced cytotoxicity of effector cells. Proteomic analysis revealed high expression of immunosuppressive secretory proteins PGE2 and galectin-9, enriched integrin pathway, and reduced proinflammatory signals like TNFα and IFNγ in female M2-like macrophages upon FPR2 agonist treatment. In addition, myeloid cells treated with FPR2 agonists induced TIM3 and PD-1 expression only in female T cells. Treatment with anti-TIM3 antibodies reversed T-cell exhaustion and stimulated their ability to infiltrate and kill pancreatic spheroids. In vivo, progression of syngeneic pancreatic tumors was significantly suppressed in FPR2 knockout (KO) female mice compared with wild-type (WT) female mice and to WT and FPR2 KO male mice. In female mice, inoculation of tumors with FPR2 KO macrophages significantly reduced tumor growth compared with WT macrophages. Overall, this study identified an immunosuppressive function of FPR2 in females, highlighting a potential sex-specific precision immunotherapy strategy.FPR2 is a sex-dependent mediator of macrophage function in pancreatic cancer and can be targeted to reprogram macrophages and stimulate antitumor immunity in females.
Genomic Uncertainty as a Burden for Reproductive Choice? The Problem of Probabilistic Causation in Non-Invasive Prenatal Testing
Authors: Jon Rueda, Mar Vallès-Poch
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:Non-Invasive Prenatal Testing for “Non-Medical” Traits: Ensuring Consistency in Ethical Decision-Making DISCLOSURE STATEMENTNo potential conflict of interest was reported by the author(s).Additional informationFundingJR thanks a La Caixa Foundation INPhINIT Retaining Fellowship (LCF/BQ/DR20/11790005).
Efficient Determination of Social Determinants of Health From Clinical Notes for Timely Identification of Suicidality Among US Veterans
Authors: Ishanu Chattopadhyay
Journal: JAMA Network Open (2023)

Avijit Mitra, MSc; Richeek Pradhan, MD; Rachel D. Melamed, PhD; Kun Chen, PhD; David C. Hoaglin, PhD; Katherine L. Tucker, PhD; Joel I. Reisman, AB; Zhichao Yang, MS; Weisong Liu, PhD; Jack Tsai, PhD; Hong Yu, PhD
Variations in Care for Early Pregnancy Loss Across Clinical Settings
Authors: Zachary F. Meisel, Courtney A. Schreiber
Journal: JAMA Network Open (2023)

Lyndsey S. Benson, MD, MS; Sarah K. Holt, PhD; John L. Gore, MD, MS; Lisa S. Callegari, MD, MPH; Anne K. Chipman, MD, MS; Larry Kessler, ScD; Vanessa K. Dalton, MD, MPH
Plasma Progerin in Patients With Hutchinson-Gilford Progeria Syndrome: Immunoassay Development and Clinical Evaluation
Authors: Leslie B. Gordon, Wendy Norris, Sarah Hamren, Robert Goodson, Jessica LeClair, Joseph Massaro, Asya Lyass, Ralph B. D’Agostino, Kelsey Tuminelli, Mark W. Kieran, Monica E. Kleinman
Journal: Circulation (2023)

Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare, fatal, premature aging disease caused by a toxic protein called progerin. Circulating progerin has not been previously detected, precluding research using readily available biological samples. This study aimed to develop a plasma progerin assay to evaluate progerin's quantity, response to progerin-targeted therapy, and relationship to patient survival.Biological samples were collected by The Progeria Research Foundation Cell and Tissue Bank from a non-HGPS cohort cross-sectionally and a HGPS cohort longitudinally. HGPS donations occurred at baseline and intermittently while treated with farnesylation inhibitors lonafarnib±pravastatin and zoledronate, within 3 sequential open-label clinical trials at Boston Children's Hospital totaling >10 years of treatment. An ultrasensitive single-molecule counting progerin immunoassay was developed with prespecified performance parameters. Intra- and interpatient group statistics were descriptive. The relationship between progerin and survival was assessed by using joint modeling with time-dependent slopes parameterization.The assay's dynamic detection range was 59 to 30 000 pg/mL (R2=0.9987). There was no lamin A cross-reactivity. Mean plasma progerin in non-HGPS participants (n=69; 39 male, 30 female; age, 0.2-71.3 years) was 351±251 pg/mL, and in drug-naive participants with HGPS (n=74; 37 female, 37 male; age, 2.1-17.5 years) was 33 261±12 346 pg/mL, reflecting a 95-fold increase in affected children (P<0.0001). Progerin levels did not differ by sex (P=0.99). Lonafarnib treatment resulted in an average per-visit progerin decrease from baseline of between 35% to 62% (all P<0.005); effects were not augmented by adding pravastatin and zoledronate. Progerin levels fell within 4 months of therapy and remained lower for up to 10 years. The magnitude of progerin decrease positively associated with patient survival (P<0.0001; ie, 15 000 pg/mL decrease yields a 63.9% decreased risk of death). For any given decrease in progerin, life expectancy incrementally increased with longer treatment duration.A sensitive, quantitative immunoassay for progerin was developed and used to demonstrate high progerin levels in HGPS plasma that decreased with lonafarnib therapy. The extent of improved survival was associated with both the magnitude of progerin decrease and duration at lower levels. Thus, plasma progerin is a biomarker for HGPS whose reduction enables short- and long-term assessment of progerin-targeted treatment efficacy.URL: https://www.gov. Unique identifiers: NCT00879034 and NCT00916747.
Evidence That Binding of Cyclic GMP to the Extracellular Domain of NKA (Sodium-Potassium ATPase) Mediates Natriuresis
Authors: Brandon A. Kemp, Nancy L. Howell, John J. Gildea, Josh D. Hinkle, Jeffrey Shabanowitz, Donald F. Hunt, Mark R. Conaway, Susanna R. Keller, Robert M. Carey
Journal: Circulation Research (2023)

Background: Extracellular renal interstitial guanosine cyclic 3’,5’-monophosphate (cGMP) inhibits renal proximal tubule (RPT) sodium (Na + ) reabsorption via Src (Src family kinase) activation. Through which target extracellular cGMP acts to induce natriuresis is unknown. We hypothesized that cGMP binds to the extracellular α1-subunit of NKA (sodium-potassium ATPase) on RPT basolateral membranes to inhibit Na + transport similar to ouabain—a cardiotonic steroid. Methods: Urine Na + excretion was measured in uninephrectomized 12-week-old female Sprague-Dawley rats that received renal interstitial infusions of vehicle (5% dextrose in water), cGMP (18, 36, and 72 μg/kg per minute; 30 minutes each), or cGMP+rostafuroxin (12 ng/kg per minute) or were subjected to pressure-natriuresis±rostafuroxin infusion. Rostafuroxin is a digitoxigenin derivative that displaces ouabain from NKA. Results: Renal interstitial cGMP and raised renal perfusion pressure induced natriuresis and increased phosphorylated Src Tyr416 and Erk 1/2 (extracellular signal-regulated protein kinase 1/2) Thr202/Tyr204 ; these responses were abolished with rostafuroxin coinfusion. To assess cGMP binding to NKA, we performed competitive binding studies with isolated rat RPTs using bodipy-ouabain (2 μM)+cGMP (10 µM) or rostafuroxin (10 µM) and 8-biotin-11-cGMP (2 μM)+ouabain (10 μM) or rostafuroxin (10 µM). cGMP or rostafuroxin reduced bodipy-ouabain fluorescence intensity, and ouabain or rostafuroxin reduced 8-biotin-11-cGMP staining. We cross-linked isolated rat RPTs with 4-N 3 -PET-8-biotin-11-cGMP (2 μM); 8-N 3 -6-biotin-10-cAMP served as negative control. Precipitation with streptavidin beads followed by immunoblot analysis showed that RPTs after cross-linking with 4-N 3 -PET-8-biotin-11-cGMP exhibited a significantly stronger signal for NKA than non–cross-linked samples and cross-linked or non–cross-linked 8-N 3 -6-biotin-10-cAMP RPTs. Ouabain (10 μM) reduced NKA in cross-linked 4-N 3 -PET-8-biotin-11-cGMP RPTs confirming fluorescence staining. 4-N 3 -PET-8-biotin-11-cGMP cross-linked samples were separated by SDS gel electrophoresis and slices corresponding to NKA molecular weight excised and processed for mass spectrometry. NKA was the second most abundant protein with 50 unique NKA peptides covering 47% of amino acids in NKA. Molecular modeling demonstrated a potential cGMP docking site in the ouabain-binding pocket of NKA. Conclusions: cGMP can bind to NKA and thereby mediate natriuresis.
Technology in the Changing Management of Diabetes in Children
Authors: Daniela Bruttomesso
Journal: New England Journal of Medicine (2023)

Management of diabetes in children younger than 6 years of age may be difficult owing to their unpredictable eating and activity patterns, low insulin requirements, and high glycemic variability. However, tight glycemic control is necessary because unmet recommended target glucose levels may have lifelong consequences.1,2 Metabolic control can be improved with the use of a closed-loop system (also termed an "artificial pancreas"), which combines an insulin pump, a continuous glucose monitoring sensor, and a control algorithm that adjusts the amount of insulin administered in real time according to input from the sensor. Currently, all commercially available closed-loop systems are hybrid, . . .
Anticipatory Governance of Noninvasive Prenatal Testing for “Non-Medical” Traits: Lessons from Regulation of Medically Assisted Reproduction
Authors: Hui Zhang, Jing Wang, Yan Qin, Chuanfeng Zhang, Bingwei Wang, Yuming Wang
Journal: The American Journal of Bioethics (2023)

This article refers to:Non-Invasive Prenatal Testing for “Non-Medical” Traits: Ensuring Consistency in Ethical Decision-Making
Public Had Most Trust in Advice From Physicians, Nurses During Pandemic
Authors: Emily Harris
Journal: JAMA (2023)

Early Respiratory Infections Tied to Premature Death Later in LifeAfter adjusting for certain baseline factors, people who had lower respiratory tract infections such as bronchitis or pneumonia before age 2 years were almost twice as likely to die from a respiratory disease by age 73 years compared with those who were not infected as children.The majority of deaths from respiratory problems were due to chronic obstructive pulmonary disease, according to the results from 3589 UK participants included in the analysis.The researchers did not find a link between lower respiratory tract infections in childhood and higher risks of premature death from other causes.The link might be driven by factors such as maternal smoking that the researchers could not account for, the authors of an associated comment noted in The Lancet.Still, the study "adds to the evidence that adults whose chronic lung disease has been attributed to smoking-related effects might also have disease resulting from childhood exposures that are largely preventable," the comment's authors wrote.
Going Back to Basics: What is the Target of Prenatal Screening?
Authors: Anne-Marie Laberge, Marie-Christine Roy, Erika Kleiderman, Vardit Ravitsky
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:Non-Invasive Prenatal Testing for “Non-Medical” Traits: Ensuring Consistency in Ethical Decision-Making Additional informationFundingThe authors would like to acknowledge funding from Genome Canada, Génome Québec, the Canadian Institutes of Health Research (CIHR), and the Stem Cell Network. Dr. Anne-Marie Laberge receives salary support from a Senior Clinician-Scientist grant from the Fonds de recherche du Québec - Santé (FRQS).
Considering the Collective in Ethical Decision-Making Concerning Non-Medical Uses of Noninvasive Prenatal Testing
Authors: Tess Johnson
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:Non-Invasive Prenatal Testing for “Non-Medical” Traits: Ensuring Consistency in Ethical Decision-Making DISCLOSURE STATEMENTNo potential conflict of interest was reported by the author(s).Additional informationFundingI would like to thank the Wellcome Trust [221719] for funding this work.
Emerging issues in probiotic safety: 2023 perspectives
Authors: Daniel Merenstein, Bruno Pot, Gregory Leyer, Arthur C. Ouwehand, Geoffrey A. Preidis, Christopher A. Elkins, Colin Hill, Zachery T. Lewis, Andi L. Shane, Niv Zmora, Mariya I. Petrova, Maria Carmen Collado, Lorenzo Morelli, Gina A. Montoya, Hania Szajewska, Daniel J. Tancredi, Mary Ellen Sanders
Journal: Gut Microbes (2023)

Probiotics are used for both generally healthy consumers and in clinical settings. However, theoretical and proven adverse events from probiotic consumption exist. New probiotic strains and products, as well as expanding use of probiotics into vulnerable populations, warrants concise, and actionable recommendations on how to work toward their safe and effective use. The International Scientific Association for Probiotics and Prebiotics convened a meeting to discuss and produce evidence-based recommendations on potential acute and long-term risks, risks to vulnerable populations, the importance for probiotic product quality to match the needs of vulnerable populations, and the need for adverse event reporting related to probiotic use. The importance of whole genome sequencing, which enables determination of virulence, toxin, and antibiotic resistance genes, as well as clear assignment of species and strain identity, is emphasized. We present recommendations to guide the scientific and medical community on judging probiotic safety.
The Potential Role of Nudging in Expanded Noninvasive Prenatal Testing
Authors: Kelsey Mumford, Nina Roesner, Benjamin E. Berkman
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:Non-Invasive Prenatal Testing for “Non-Medical” Traits: Ensuring Consistency in Ethical Decision-Making DISCLOSURE STATEMENTThe views herein are those of the authors and do not represent the views or policies of the Department of Health and Human Services or the National Institutes of Health.Additional informationFundingThis research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health.
To Invade the Brain, Pathogens Exploit Pain, Immune Cells
Authors: Emily Harris
Journal: JAMA (2023)

Early Respiratory Infections Tied to Premature Death Later in LifeAfter adjusting for certain baseline factors, people who had lower respiratory tract infections such as bronchitis or pneumonia before age 2 years were almost twice as likely to die from a respiratory disease by age 73 years compared with those who were not infected as children.The majority of deaths from respiratory problems were due to chronic obstructive pulmonary disease, according to the results from 3589 UK participants included in the analysis.The researchers did not find a link between lower respiratory tract infections in childhood and higher risks of premature death from other causes.The link might be driven by factors such as maternal smoking that the researchers could not account for, the authors of an associated comment noted in The Lancet.Still, the study "adds to the evidence that adults whose chronic lung disease has been attributed to smoking-related effects might also have disease resulting from childhood exposures that are largely preventable," the comment's authors wrote.
Novel Once-Weekly Basal Insulin Fc Achieved Similar Glycemic Control With a Safety Profile Comparable to Insulin Degludec in Patients With Type 1 Diabetes
Authors: Christof M. Kazda, Juliana M. Bue-Valleskey, Jenny Chien, Qianyi Zhang, Emmanuel Chigutsa, William Landschulz, Paula Wullenweber, Axel Haupt, Dominik Dahl
Journal: Diabetes Care (2023)

Basal Insulin Fc (BIF; insulin efsitora alfa; LY3209590), a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for once-weekly basal insulin administration. This phase 2 study assessed safety and efficacy of BIF versus degludec in 265 patients with type 1 diabetes (T1D) using multiple daily injections.
Spatial mapping reveals granuloma diversity and histopathological superstructure in human tuberculosis
Authors: Andrew J. Sawyer, Ellis Patrick, Jarem Edwards, James S. Wilmott, Timothy Fielder, Qianting Yang, Daniel L. Barber, Joel D. Ernst, Warwick J. Britton, Umaimainthan Palendira, Xinchun Chen, Carl G. Feng
Journal: The Journal of Experimental Medicine (2023)

The hallmark of tuberculosis (TB) is the formation of immune cell-enriched aggregates called granulomas. While granulomas are pathologically diverse, their tissue-wide heterogeneity has not been spatially resolved at the single-cell level in human tissues. By spatially mapping individual immune cells in every lesion across entire tissue sections, we report that in addition to necrotizing granulomas, the human TB lung contains abundant non-necrotizing leukocyte aggregates surrounding areas of necrotizing tissue. These cellular lesions were more diverse in composition than necrotizing lesions and could be stratified into four general classes based on cellular composition and spatial distribution of B cells and macrophages. The cellular composition of non-necrotizing structures also correlates with their proximity to necrotizing lesions, indicating these are foci of distinct immune reactions adjacent to necrotizing granulomas. Together, we show that during TB, diseased lung tissue develops a histopathological superstructure comprising at least four different types of non-necrotizing cellular aggregates organized as satellites of necrotizing granulomas.
Complications and treatment errors involving periodontal tissues related to orthodontic therapy
Authors: Karin Jepsen, Anton Sculean, Søren Jepsen
Journal: Periodontology 2000 (2023)

Abstract In this review, typical clinical complications involving periodontal tissues are illustrated that can be encountered in conjunction with orthodontic therapy (OT). Special considerations are given for various clinical scenarios, such as the patient presenting in periodontal health, with periodontitis, or with mucogingival conditions. While some of the complications are seen as common side effects of OT, other, more severe, problems that could have been avoided may be viewed as treatment errors. Recommendations are made on how to prevent these complications, based on the currently available evidence, on clinical practice guidelines, and on expert opinion. In conclusion, while there are several areas in which OT can have unwanted adverse effects on periodontal/mucogingival conditions, there is also great potential for synergies, offering opportunities for close cooperation between the two specialties (periodontics and orthodontics) for the benefit of patients affected by tooth malpositioning and /or periodontal or mucogingival problems.
A Review of RRx-001: A Late-Stage Multi-Indication Inhibitor of NLRP3 Activation and Chronic Inflammation
Authors: Nanthini Jayabalan, Bryan Oronsky, Pedro Cabrales, Tony Reid, Scott Caroen, Aishwarya M. Johnson, Natalia A. Birch, John D. O’Sullivan, Richard Gordon
Journal: Drugs (2023)

Chronic unresolving inflammation is emerging as a key underlying pathological feature of many if not most diseases ranging from autoimmune conditions to cardiometabolic and neurological disorders. Dysregulated immune and inflammasome activation is thought to be the central driver of unresolving inflammation, which in some ways provides a unified theory of disease pathology and progression. Inflammasomes are a group of large cytosolic protein complexes that, in response to infection- or stress-associated stimuli, oligomerize and assemble to generate a platform for driving inflammation. This occurs through proteolytic activation of caspase-1-mediated inflammatory responses, including cleavage and secretion of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and initiation of pyroptosis, an inflammatory form of cell death. Several inflammasomes have been characterized. The most well-studied is the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, so named because the NLRP3 protein in the complex, which is primarily present in immune and inflammatory cells following activation by inflammatory stimuli, belongs to the family of nucleotide-binding and oligomerization domain (Nod) receptor proteins. Several NLRP3 inflammasome inhibitors are in development, all with multi-indication activity. This review discusses the current status, known mechanisms of action, and disease-modifying therapeutic potential of RRx-001, a direct NLRP3 inflammasome inhibitor under investigation in several late-stage anticancer clinical trials, including a phase 3 trial for the treatment of third-line and beyond small cell lung cancer (SCLC), an indication with no treatment, in which RRx-001 is combined with reintroduced chemotherapy from the first line, carboplatin/cisplatin and etoposide (ClinicalTrials.gov Identifier: NCT03699956). Studies from multiple independent groups have now confirmed that RRx-001 is safe and well tolerated in humans. Additionally, emerging evidence in preclinical animal models suggests that RRx-001 could be effective in a wide range of diseases where immune and inflammasome activation drives disease pathology.
Change in Albuminuria and GFR Slope as Joint Surrogate End Points for Kidney Failure: Implications for Phase 2 Clinical Trials in CKD
Authors: Hiddo J.L. Heerspink, Lesley A. Inker, Hocine Tighiouart, Willem H. Collier, Benjamin Haaland, Jiyu Luo, Gerald B. Appel, Tak Mao Chan, Raymond O. Estacio, Fernando Fervenza, Jürgen Floege, Enyu Imai, Tazeen H. Jafar, Julia B. Lewis, Philip Kam-Tao Li, Francesco Locatelli, Bart D. Maes, Annalisa Perna, Ronald D. Perrone, Manuel Praga, Francesco P. Schena, Christoph Wanner, Di Xie, Tom Greene
Journal: Journal of the American Society of Nephrology (2023)

Changes in albuminuria and GFR slope are individually used as surrogate end points in clinical trials of CKD progression, and studies have demonstrated that each is associated with treatment effects on clinical end points. In this study, the authors sought to develop a conceptual framework that combines both surrogate end points to better predict treatment effects on clinical end points in Phase 2 trials. The results demonstrate that information from the combined treatment effects on albuminuria and GFR slope improves the prediction of treatment effects on the clinical end point for Phase 2 trials with sample sizes between 100 and 200 patients and duration of follow-up ranging from 1 to 2 years. These findings may help inform design of clinical trials for interventions aimed at slowing CKD progression.